膳食干预肠道菌群预防代谢性疾病

Wild-type normal chow
Shanghai Jiao Tong University
动物实验
C57BL/6 mice
Wild-type C57BL/6 mice
雄性
高脂饲料 (HFD) 60% fat
低脂饲料 (LFD) 10% fat
HFD
吃饱 30
HFD, CR
七成饱 30
HFD, Ex
IIya Mechnikov Nobel Laureate 1908
“粪毒入血， 百病蜂起”
Shanghai Jiao Tong University
肠道菌群结构失调与代谢综合征
Cani, 2009
Shanghai Jiao Tong University
肠道菌群控制能量代谢基因表达
Backhed, F., et al., The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A, 2004. 101:15718-15723.
Shanghai Jiao Tong University
脂多糖结合蛋白连接抗原载荷量和宿主炎性反应的生物标识物
保持健康的关键: 减少肠道里的毒素和抗原的量
Shanghai Jiao Tong University
营养干预下的菌群变化
C57BL/6J mice （male,10 weeks）
Group A (n=10)
细胞毒素、遗传毒素、免疫毒素 -肝肠循环 -肠屏障受损
—— 中医观念 Symbiosis vs. Dysbiosis “Fecal toxins into bloodstream will lead to all kinds of diseases”
——Concept from Traditional Chinese Medicine (TCM)
Backhed, F., et al., Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A, 2007. 104: 979-984. Turnbaugh, P.J., et al., An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 2006. 444(7122): p. 1027-1031. Turnbaugh, P.J., et al., Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe, 2008. 3: 213-223.
最高寿命可延长50%
Shanghai Jiao Tong University
Midlife gut microbiota and health states 中年菌群结构与健康指标的关系
HFD/HFD,Ex LFD/LFD,Ex/HFD,CR LFD,CR
与寿命相关的细菌种类
Shanghai Jiao Tong University
Shanghai Jiao Tong University
慢性病的肠道起源 Gut Origin of Chronic Diseases
“Later he took up the study of the flora of the human intestine and developed a theory that senility is due to poisoning of the body by the products of certain of these bacteria. To prevent the multiplication of these organisms he proposed a diet containing milk fermented by bacilli which produce large amounts of lactic acid and for a time this diet became widely popular.” -http://nobelprize.org/
内毒素
Molecular Inflammation induced by endotoxin
内毒素诱导的分子炎症
Inflammation induced by diet-disrupted gut microbiota
Shanghai Jiao Tong University
菌群结构失调诱发慢性炎症
weeks
Shanghai Jiao Tong University
体重与糖耐量的变化
High-fat Diet
Normal Chow Diet
Normal Chow Diet
Normal Chow Diet
Shanghai Jiao Tong University
UniFrac Analysis 菌群的变化轨迹
肠道菌群成为预防和治疗代谢性疾病的新靶标
Human Superorganisms 正确认识自己的身体－“超级生物体”
人体内生活着1-2公斤 人基因组 细菌
• 90%在肠道里
先天遗传
诺贝尔奖得主-里德伯格, Science 2000
人体的细胞组成 药品
• 细胞
体 质 10%人细胞+90%细菌
食品
健康
亚健康
疾病
人体的基因组成
• 2.5万个人的基因 • 3百多万个微生物基因 • 丰富而活跃的代谢活动 后天养成
Cani, P.D., Neyrinck, A.M., Fava, F., Knauf, C., Burcelin, R.G., Tuohy, K.M. et al. (2007b) Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 50: 2374-2383 Cani, P.D, et al.,(2008) Changes in gut microbiota control metabolic endotoxemia-induced inflamation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57: 1470-1482 Cani, P.D, et al.,(2009) Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58:1091-1103
Cani, P.D., Amar, J., Iglesias, M.A., Poggi, M., Knauf, C., Bastelica, D. et al. (2007a) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56: 1761-1772.
吃饱+锻炼 30
LFD
吃饱 30
LFD, CR
七成饱 30
LFD, Ex
吃饱+锻炼 30
Diet modulation of lifespan
Shanghai Jiao Tong University
膳食改变寿命
1073 958 888 913
800
712
LFD,CR 3.54 年 vs. HFD 2.36年
Shanghai Jiao Tong University
动物实验
对照鼠
好基因
敲除鼠
坏基因
高脂饲料
坏食物
植物饲料
高脂饲料
坏食物
植物饲料
好食物
好食物
两种基因 X 两种饲料 饲喂6个月
Shanghai Jiao Tong University
好基因+坏食物病得最重！
Growth Curve
Phenotype Data
Shanghai Jiao Tong University
Shanghai Jiao Tong University
脂多糖结合蛋白LBP在营养干预下的变化
Shanghai Jiao Tong University
脂多糖结合蛋白连接抗原载荷量和宿主炎性反应的生物标识物
保持健康的关键: 减少肠道里的毒素和抗原的量
Shanghai Jiao Tong University
Apoa-1 knock-out mouse Apoa-1 基因敲除鼠
Apoa-1 基因
C57BL/6 mice
敲除
Apoa-1-/- mice
高密度脂蛋白水平低
易感动脉粥样硬化 先天性胰岛素抵抗
Apolipoprotein A-Ⅰ
敲除小鼠 Apoa-l gene的策略 (Williamson, 1992, PNAS)
Food intake Glucose Tolerance Test
Shanghai Jiao Tong University
Diet is shaping gut microbiota 饮食决定肠道菌群结构，基因作用很小
Apoa-Ⅰ-/- /HFD Apoa-Ⅰ-/- /NC 敲除鼠/高脂饲料 敲除鼠/植物饲料
双歧杆菌-有益菌
正
% of Total Sequences
4 3.5 3 2.5 2 1.5 1 0.5 0
**P<0.01 *P<0.05
硫酸盐还原菌-有害菌
*
邪
* *
ApoA-Ⅰ -/high fat diet
ApoA-Ⅰ -/normal chow
Wild-type high fat diet
膳食干预肠道菌群预防代谢性疾病
Dietary Modulation of Gut Microbiota for Preventive management of Metabolic Diseases
赵立平 Liping Zhao 上海交通大学生命科学技术学院
上海系统生物医学研究中心
Shanghai Jiao Tong University
Normal Chow（fat 5.2%）
Group B (n=10)
High fat diet（fat 34.9%）
22 weeks
12 weeks
Group B（n=9)
Normal Chow（fat 5.2%）
10 weeks
C57BL/6 mice
-2 0
2
4
Байду номын сангаас
6
8 10 12 14 16 18 20 22
肠道微生物组
Joshua Lederberg Nobel Laureate 1958
肠道菌群——人体后天获得的“第二个基因组”
Gut Microbiota-Second genome acquired after birth
Shanghai Jiao Tong University
“慢性病的肠道起源” “人体系统生物学方法”
Wt/NC Wt/HFD 野生型/高脂饲料 野生型/植物饲料
Shanghai Jiao Tong University
新一代革命性测序技术
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1个技术员，1台新设备 100 台老一代测序仪
NATURE METHODS ，16 | VOL.5 NO.1 | JANUARY 2008
15
Shanghai Jiao Tong University
Jeffery Gordon
Shanghai Jiao Tong University
慢性炎症与衰老和老年病的关系 Inflammation and Age-related Diseases
低度、系统性的慢性炎症
代谢性疾病 糖尿病 肥胖
炎性衰老
Endotoxin-the most common immunotoxin 内毒素-最常见的免疫毒素